Review
Oncology
Paulina Stefaniuk, Julia Onyszczuk, Agnieszka Szymczyk, Monika Podhorecka
Summary: CLL, the most common type of leukemia in adults in western countries, shows heterogeneity in clinical course and response to treatment. TP53 aberrations are the most important factors of poor prognosis. Treatment of patients with TP53-deficiency requires drugs promoting cell death independently of TP53.
CANCER MANAGEMENT AND RESEARCH
(2021)
Article
Oncology
Miguel Quijada-Alamo, Claudia Perez-Carretero, Maria Hernandez-Sanchez, Ana-Eugenia Rodriguez-Vicente, Ana-Belen Herrero, Jesus-Maria Hernandez-Sanchez, Marta Martin-Izquierdo, Sandra Santos-Minguez, Monica Del Rey, Teresa Gonzalez, Araceli Rubio-Martinez, Alfonso Garcia de Coca, Julio Davila-Valls, Jose-Angel Hernandez-Rivas, Helen Parker, Jonathan C. Strefford, Rocio Benito, Jose-Luis Ordonez, Jesus-Maria Hernandez-Rivas
Summary: Our study found that concurrent biallelic ATM and TP53 loss is mutually exclusive in CLL, while monoallelic del(11q) and TP53 alterations significantly co-occur in a subset of patients with poor prognosis. CRISPR/Cas9-edited CLL cell lines revealed that combined del(11q) and TP53 mutations provide clonal advantage, whereas CLL cells with biallelic ATM and TP53 loss fail to compete in xenotransplants. Furthermore, CLL cell lines with del(11q) and TP53 mutations show partial responses to B cell receptor signaling inhibitors, indicating potential benefit from ATR inhibition.
CLINICAL AND TRANSLATIONAL MEDICINE
(2021)
Review
Oncology
Florence Nguyen-Khac
Summary: Although the 17p deletion is rare in treatment-naive CLL, its frequency is higher in refractory/relapsed CLL, especially in patients undergoing chemotherapy. TP53 disruption is the strongest prognostic factor for chemotherapy resistance, and the use of Bruton tyrosine kinase inhibitors and BCL2 inhibitors is recommended. Rare cases of CLL may also have translocation or gain of the MYC oncogene, and double-hit CLL (with del(17p) and MYC gain) has a very poor prognosis. The prognostic impact of TP53 disruption with MYC aberrations in patients receiving targeted therapies needs to be evaluated.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Riccardo Bomben, Francesca Maria Rossi, Filippo Vit, Tamara Bittolo, Tiziana D'Agaro, Antonella Zucchetto, Erika Tissino, Federico Pozzo, Elena Vendramini, Massimo Degan, Eva Zaina, Ilaria Cattarossi, Paola Varaschin, Paola Nanni, Michele Berton, Alessandra Braida, Jerry Polesel, Jared A. Cohen, Enrico Santinelli, Annalisa Biagi, Massimo Gentile, Fortunato Morabito, Gilberto Fronza, Gabriele Pozzato, Giovanni D'Arena, Jacopo Olivieri, Pietro Bulian, Chris Pepper, Anna Hockaday, Anna Schuh, Peter Hillmen, Davide Rossi, Annalisa Chiarenza, Francesco Zaja, Francesco Di Raimondo, Giovanni Del Poeta, Valter Gattei
Summary: This study retrospectively analyzed the clinical impact of TP53 mutations in chronic lymphocytic leukemia, finding that TP53 mutations affect overall survival regardless of variant allele frequency. The results of the study suggest updating the definition of TP53 mutated CLL for clinical purposes.
CLINICAL CANCER RESEARCH
(2021)
Review
Oncology
Thierry Soussi, Panagiotis Baliakas
Summary: Locus-specific databases are essential tools for basic and clinical research. They gather extensive information curated by experts from the literature. TP53 mutation databases play a crucial role in the validation and diagnosis of TP53 variants in chronic lymphocytic leukemia.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Veronika Mancikova, Michaela Pesova, Sarka Pavlova, Robert Helma, Kristyna Zavacka, Vaclav Hejret, Petr Taus, Jakub Hynst, Karla Plevova, Jitka Malcikova, Sarka Pospisilova
Summary: Abnormalities in the TP53 gene are the most significant biomarker in chronic lymphocytic leukemia (CLL). Changes in p53 protein modifications can also influence its function, even in the wild-type protein. This study explores the impact of p53 protein phosphorylations on p53 function and suggests that reduced phosphorylation of wild-type p53 in CLL cells leads to behavior similar to TP53 mutants after DNA damage. These findings are linked to ATM locus defects and higher basal activity of the hypoxia pathway.
MOLECULAR ONCOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Kristan V. Piroeva, Charlotte Mcdonald, Charalampos Xanthopoulos, Chelsea Fox, Christopher T. Clarkson, Jan-Philipp Mallm, Yevhen Vainshtein, Luminita Ruje, Lara C. Klett, Stephan Stilgenbauer, Daniel Mertens, Efterpi Kostareli, Karsten Rippe, Vladimir B. Teif
Summary: This study compared the nucleosome positions in chronic lymphocytic leukemia (CLL) patients and healthy individuals, and found significant changes in nucleosome positioning in CLL. The spacing between nucleosomes was shortened, and changes in nucleosome occupancy were linked to chromatin remodeling and reduced DNA methylation. Nucleosome positioning can be used to classify CLL subtypes and monitor disease progression.
Article
Biochemistry & Molecular Biology
Erhan Aptullahoglu, Jonathan P. Wallis, Helen Marr, Scott Marshall, Nick Bown, Elaine Willmore, John Lunec
Summary: Chronic lymphocytic leukemia (CLL) is a genetically and clinically heterogeneous malignancy affecting older individuals. Novel targeted therapies are needed for CLL patients who are treatment resistant or relapse. This study found that SF3B1 mutations were associated with poor response to the MDM2 inhibitor RG7388 in CLL patients. Patients with wild-type SF3B1 and TP53 are more likely to benefit from treatment with MDM2 inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, General & Internal
Barbara Eichhorst, Carsten U. Niemann, Arnon P. Kater, Moritz Fuerstenau, Julia von Tresckow, Can Zhang, Sandra Robrecht, Michael Gregor, Gunnar Juliusson, Patrick Thornton, Philipp B. Staber, Tamar Tadmor, Vesa Lindstrom, Caspar da Cunha-Bang, Christof Schneider, Christian B. Poulsen, Thomas Illmer, Bjoern Schoettker, Thomas Noesslinger, Ann Janssens, Ilse Christiansen, Michael Baumann, Henrik Frederiksen, Marjolein van der Klift, Ulrich Jaeger, Maria B. L. Leys, Mels Hoogendoorn, Kourosh Lotfi, Holger Hebart, Tobias Gaska, Harry Koene, Lisbeth Enggaard, Jereon Goede, Josien C. Regelink, Anouk Widmer, Florian Simon, Nisha De Silva, Anna-Maria Fink, Jasmin Bahlo, Kirsten Fischer, Clemens-Martin Wendtner, Karl A. Kreuzer, Matthias Ritgen, Monika Brueggemann, Eugen Tausch, Mark-David Levin, Marinus van Oers, Christian Geisler, Stephan Stilgenbauer, Michael Hallek
Summary: In fit patients with CLL, venetoclax-obinutuzumab, with or without ibrutinib, showed superior results compared to chemoimmunotherapy as a first-line treatment, with higher rates of undetectable minimal residual disease and progression-free survival.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Editorial Material
Oncology
Riccardo Bomben, Antonella Zucchetto, Massimo Gentile, Valter Gattei
Summary: Patients with chronic lymphocytic leukemia carrying a single TP53 hit (chromosome 17p deletion or single TP53 mutation) show better survival outcomes on ibrutinib therapy compared to those with multiple TP53 hits. Testing for TP53 deletion/mutation using a combination of FISH and deep next-generation sequencing is recommended for accurate patient evaluation.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Silvia Ramos-Campoy, Anna Puiggros, Joanna Kamaso, Silvia Bea, Sandrine Bougeon, Maria Jose Larrayoz, Dolors Costa, Helen Parker, Gian Matteo Rigolin, Maria Laura Blanco, Rosa Collado, Idoya Ancin, Rocio Salgado, Marco A. Moro-Garcia, Tycho Baumann, Eva Gimeno, Carol Moreno, Marta Salido, Xavier Calvo, Maria Jose Calasanz, Antonio Cuneo, Florence Nguyen-Khac, David Oscier, Claudia Haferlach, Jonathan C. Strefford, Jacqueline Schoumans, Blanca Espinet
Summary: Chromothripsis (cth) has been associated with a poor prognosis in chronic lymphocytic leukemia (CLL) patients. Despite its correlation with high genome instability, previous studies have not evaluated the role of cth in the context of genomic complexity. We analyzed 33 CLL patients with cth and compared them with 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared, and the prognostic value of cth was assessed.
Article
Genetics & Heredity
Alba Rodriguez-Meira, Ruggiero Norfo, Sean Wen, Agathe L. Chedeville, Haseeb Rahman, Jennifer O'Sullivan, Guanlin Wang, Eleni Louka, Warren W. Kretzschmar, Aimee Paterson, Charlotte Brierley, Jean-Edouard Martin, Caroline Demeule, Matthew Bashton, Nikolaos Sousos, Daniela Moralli, Lamia Subha Meem, Joana Carrelha, Bishan Wu, Angela Hamblin, Helene Guermouche, Florence Pasquier, Christophe Marzac, Francois Girodon, William Vainchenker, Mark Drummond, Claire Harrison, J. Ross Chapman, Isabelle Plo, Sten Eirik W. Jacobsen, Bethan Psaila, Supat Thongjuea, Ileana Antony-Debre, Adam J. Mead
Summary: This study analyzes hematopoietic stem/progenitor cells from patients with secondary acute myeloid leukemia (sAML) transforming from myeloproliferative neoplasm. They find that chronic inflammation suppresses TP53 wild-type cells while enhancing the fitness advantage of TP53-mutant cells, promoting genetic evolution. These findings will aid in the development of risk-stratification, early detection, and treatment strategies for TP53-mutant leukemia.
Article
Hematology
Hua-Jay J. Cherng, Raamis Khwaja, Rashmi Kanagal-Shamanna, Guilin Tang, Jan Burger, Philip Thompson, Alessandra Ferrajoli, Zeev Estrov, Koji Sasaki, Deepa Sampath, Xuemei Wang, Hagop Kantarjian, Michael Keating, William G. Wierda, Nitin Jain
Summary: Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated patients with TP53-altered chronic lymphocytic leukemia (CLL). A retrospective analysis of patients with CLL treated with BTKi was performed, and the results showed that variant allele frequency (VAF) of TP53 mutation (TP53-m) or percentage of cells with deletion of chromosome 17p [del(17p)] did not significantly influence the efficacy of first-line BTKi, although there was a trend towards shorter progression-free survival (PFS) with increasing karyotypic complexity.
AMERICAN JOURNAL OF HEMATOLOGY
(2022)
Article
Oncology
Asma Ounalli, Imen Moumni, Amal Mechaal, Aya Chakroun, Mbarka Barmat, Rim El Elj Rhim, Samia Menif, Ines Safra
Summary: This study found a correlation between the single nucleotide polymorphism (rs1042522) in the TP53 gene and the risk susceptibility as well as severity of CLL in Tunisian patients.
FRONTIERS IN ONCOLOGY
(2023)
Review
Oncology
Billy Michael Chelliah Jebaraj, Stephan Stilgenbauer
Summary: Telomeres play a crucial role in chronic lymphocytic leukemia (CLL), with their dysfunction shaping the disease progression. Members of the shelterin complex and TERT activation are closely associated with CLL cell survival and proliferation.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Joanna Gora-Tybor, Aleksandra Golos, Damian Mikulski, Grzegorz Helbig, Tomasz Sacha, Krzysztof Lewandowski, Joanna Niesiobedzka-Krezel, Maria Bieniaszewska, Hubert Wysoglad, Olga Grzybowska-Izydorczyk, Ilona Seferynska, Marta Sobas, Maria Czyzewska, Agnieszka Michalska, Waldemar Sawicki, Malwina Mazur, Marek Hus, Ewa Bodzenta, Magdalena Olszewska-Szopa, Martyna Wlodarczyk, Elzbieta Patkowska, Wojciech Swistek, Krzysztof Jamroziak
Summary: In this study, predictors of response to ruxolitinib therapy in Polish myelofibrosis patients were investigated. Leukocytosis < 25 G/L, reticulin fibrosis MF 1, shorter time from MF diagnosis to ruxolitinib start, and platelets >150 G/L were correlated with better response to ruxolitinib. Identifying predictive factors for ruxolitinib response is important for identifying patients who are less likely to respond.
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Article
Oncology
Marco Dicanio, Matteo Giaccherini, Alyssa Clay-Gilmour, Angelica Macauda, Juan Sainz, Mitchell J. Machiela, Malwina Rybicka-Ramos, Aaron D. Norman, Agata Tyczynska, Stephen J. Chanock, Torben Barington, Shaji K. Kumar, Parveen Bhatti, Wendy Cozen, Elizabeth E. Brown, Anna Suska, Eva K. Haastrup, Robert Z. Orlowski, Marek Dudzinski, Ramon Garcia-Sanz, Marcin Kruszewski, Joaquin Martinez-Lopez, Katia Beider, Elzbieta Iskierka-Jazdzewska, Matteo Pelosini, Sonja Berndt, Malgorzata Razny, Krzysztof Jamroziak, S. Vincent Rajkumar, Artur Jurczyszyn, Annette Juul Vangsted, Pilar Garrido Collado, Ulla Vogel, Jonathan N. Hofmann, Mario Petrini, Aleksandra Butrym, Susan L. Slager, Elad Ziv, Edyta Subocz, Graham G. Giles, Niels Frost Andersen, Grzegorz Mazur, Marzena Watek, Fabienne Lesueur, Michelle A. T. Hildebrandt, Daria Zawirska, Lene Hyldahl Ebbesen, Herlander Marques, Federica Gemignani, Charles Dumontet, Judit Varkonyi, Gabriele Buda, Arnon Nagler, Agnieszka Druzd-Sitek, Xifeng Wu, Katalin Kadar, Nicola J. Camp, Norbert Grzasko, Rosalie G. Waller, Celine Vachon, Federico Canzian, Daniele Campa
Summary: The aim of this study was to identify novel pleiotropic variants involved in multiple myeloma (MM) risk. Through analysis of 28,684 single nucleotide polymorphisms (SNPs), DNAJB4-rs34517439-A was found to be associated with an increased risk of developing MM.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Review
Biotechnology & Applied Microbiology
Pawel Robak, Tadeusz Robak
Summary: In recent years, there have been significant advancements in the treatment of chronic lymphocytic leukemia (CLL), including the use of novel targeted drugs and monoclonal antibodies. Combination therapies with different agents have shown high activity in both treatment naive and relapsed/refractory CLL patients. However, more research is needed to determine the optimal sequencing of therapies and selection of upfront treatment options.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2023)
Review
Pharmacology & Pharmacy
Aleksandra Golos, Joanna Gora-Tybor, Tadeusz Robak
EXPERT OPINION ON INVESTIGATIONAL DRUGS
(2023)
Review
Pharmacology & Pharmacy
Tadeusz Robak, Pawel Robak
Summary: This article summarizes recent achievements in the treatment of relapsed and refractory hairy cell leukemia. The growing understanding of HCL biology has led to the development of several new targeted drugs, which have shown promising efficacy in early clinical trials.
EXPERT OPINION ON INVESTIGATIONAL DRUGS
(2023)
Article
Oncology
Talha Munir, Carol Moreno, Carolyn Owen, George Follows, Ohad Benjamini, Ann Janssens, Mark-David Levin, Anders Osterborg, Tadeusz Robak, Martin Simkovic, Don Stevens, Sergey Voloshin, Vladimir Vorobyev, Munci Yagci, Loic Ysebaert, Keqin Qi, Qianya Qi, Lori Parisi, Srimathi Srinivasan, Natasha Schuier, Kurt Baeten, Angela Howes, Donne Bennett Caces, Carsten U. U. Niemann, Arnon P. P. Kater
Summary: In the GLOW study, fixed-duration ibrutinib + venetoclax treatment showed better progression-free survival (PFS) compared to chlorambucil + obinutuzumab in older/comorbid patients with previously untreated CLL. This analysis examines the kinetics of minimal residual disease (MRD) and its predictive value for PFS, which has not been evaluated for ibrutinib + venetoclax treatment.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Letter
Oncology
Tadeusz Robak, Jaroslaw D. Kasprzak, Dorota Jesionek-Kupnicka, Michal Soin, Pawel Robak
LEUKEMIA & LYMPHOMA
(2023)
Editorial Material
Oncology
Tadeusz Robak
LEUKEMIA & LYMPHOMA
(2023)
Article
Pharmacology & Pharmacy
Pawel Robak, Magda Witkowska, Anna Wolska-Washer, Tadeusz Robak
Summary: Orelabrutinib is a promising drug for the treatment of B-cell indolent lymphoid malignancies and autoimmune disorders, with high selectivity, good efficacy, and excellent safety profile.
EXPERT OPINION ON DRUG DISCOVERY
(2023)
Review
Biochemistry & Molecular Biology
Magdalena Witkowska, Agata Majchrzak, Pawel Robak, Anna Wolska-Washer, Tadeusz Robak
Summary: PI3K & delta; inhibitors are novel agents used to treat B-cell malignancies by inhibiting enzymes in the PI3K/AKT/mTOR pathway. Idelalisib is an effective inhibitor for B-cell lymphoid malignancies.
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
(2023)
Article
Oncology
Mikkael A. Sekeres, Pau Montesinos, Jan Novak, Jianxiang Wang, Deepa Jeyakumar, Benjamin Tomlinson, Jiri Mayer, Erin Jou, Tadeusz Robak, David C. Taussig, Herve Dombret, Akil Merchant, Naveed Shaik, Thomas O'Brien, Whijae Roh, Xueli Liu, Wendy Ma, Christine G. DiRienzo, Geoffrey Chan, Jorge E. Cortes
Summary: This is the primary report of the BRIGHT AML 1019 clinical trial, which investigated the use of glasdegib in combination with intensive or non-intensive chemotherapy for untreated acute myeloid leukemia patients. The study found that there was no significant improvement in overall survival when glasdegib was added to either chemotherapy regimen. The occurrence of treatment-emergent adverse events was similar between the glasdegib and placebo groups. Clinical trial registration: ClinicalTrials.gov: NCT03416179.
Letter
Oncology
Tara Cochrane, Alicia Enrico, David Gomez-Almaguer, Evgueniy Hadjiev, Ewa Lech-Maranda, Tamas Masszi, Eugene Nikitin, Tadeusz Robak, Robert Weinkove, Shang-Ju Wu, Beenish S. Manzoor, Todd Busman, Madhavi Pai, Viktor Komlosi, Mary Ann Anderson
LEUKEMIA & LYMPHOMA
(2023)
Meeting Abstract
Oncology
Dana Cholujova, Gabor Beke, Teru Hideshima, Lubos Klucar, Merav Leiba, Krzysztof Jamroziak, Paul Richardson, Efstathios Kastritis, David Dorfman, Kenneth Anderson, Jana Jakubikova
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Meeting Abstract
Oncology
Tadeusz Kubicki, Dominik Dytfeld, Tomasz Wrobel, Krzysztof Jamroziak, Pawel Robak, Jaroslaw Czyz, Agata Tyczynska, Agnieszka Druzd-Sitek, Krzysztof Giannopoulos, Adam Nowicki, Anna Lojko-Dankowska, Magdalena Matuszak, Lidia Gil, Bartosz Pula, Justyna Rybka, Lidia Usnarska-Zubkiewicz, Olga Czabak, Andrew Stefka, Ken Jiang, Benjamin Derman, Andrzej Jakubowiak
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)